Azatyrosine (L-b-(5-hydroxy-2-pyridyl)alanine), an antibiotic from Streptomyces chibanensis (Inouye, S.; Shomura, T.; Tsuruoka, T.; Ogawa Y.; Watanabe, H.; Yoshida, J.; Niida, T. Chem. Pharm. Bull. 1975, 23, 2669.), was first reported to suppress the growth of NIH 3T3 cells transformed by c-Ha-ras, c-Ki-ras, N-ras, or c-raf oncogene while having essentially no effect on the wild type cells (Shindo-Okada, N.; Makabe, O.; Nagallara, H.; Nishimura, S. Mol. Carcinogen 1989, 2, 159.). Those azatyrosine-treated transformed cells that survived reverted to an apparently normal phenotype, the normal appearance and growth characteristics of the cells persisted for months after removal of the compound (Krzyzosiak, W. J.; Shindo-Okada, N.; Teshima, H.; Nakajima, K.; Nishimura, S. Proc, Natl. Acad. Sci. U.S.A. 1992, 89, 4879.), and some of the revertant clone demonstrated complete loss of tumorigenicity on nude mice. Studies also proved that this compound is involved in the regulation of other oncogenic cell growth (Chung, D. L.; Brandt-llauf, P.; Murphye, R. B.; Nishimura, S.; Yamaizumi, Z.; Weinst:ein, l. B.; Pincuf, M. R. Anticancer Res. 1991, 11, 1373. Kyprianou, N.; Taylor-Papadimitriou, J. Oncogene 1992, 7, 57. Fujita-Yoshigaki, J.; Yokoyama, S.; Shindo-Okada, N.; Nlshimura, S. Oncogene 1992, 7, 2019. Nomura, T.; Ryoyama, K.; Okada, G.; Matano, S.; Nakamura, S.; Kameyama, T. Jpn. J. Cancer Res. 1992, 83, 851. Campa, M. J.; Glickman, J. F.; Yamamoto, K.; Chang, K. J. Proc, Natl. Acad. Sci. U.S.A. 1992, 89, 7654. Benoit, R. M.; Eiseman, J.; Jacobs, S. C.; Kyprianou, N. Urology 1995, 46, 370.). In addition, L-azatyrosine inhibits 7,12-dimethylbenza!anthracene or methylnitrosourea-induced carcinogenesis in mice harboring a normal c-Ha-ras gene ( Izawa, M.; Takaysma, S.; Shindo-Okada, N.; Doi, S.; Kimura, M.; Katsuki, M.; Nishimura, S. Cancer Res. 1992, 52, 1628.). The high reversion efficiency toward oncogenic transformed cells combined with low toxicity to normal cells suggested azatyrosine to be a new lead for developing anticancer agents (Ye, B.; Otaka, A.; Jr. Bruke, T. R. Synlett 1996, 459. Copper, M. S.; Seton, A. W.; Stevens, M. F. G.; Westwell, A. D. Bioorg. Med. Chem. Lett. 1996, 6, 2613.).
Although azatyrosine exhibited selective toxicity against ras-transformed tumor cells, the potential of this compound in cancer treatment is limited due to its potency. Relatively high concentrations up to 1-2 mM are necessary for the actvity (Shindo-Okada, N.; Makabe, O.; Nagallara, H.; Nishimura, S. Mol. Carcinogen 1989, 2, 159. Fujita-Yoshigaki, J.; Yokoyama, S.; Shindo-Okada, N.; Nlshimura, S. Oncogene 1992, 7, 2019. Benoit, R. M.; Eiseman, J.; Jacobs, S. C.; Kyprianou, N. Urology 1995, 46, 370.). It is believed that low activity demonstrated by azatyrosine is partially due to its low intracellular bioavailability, which is probably due to its amphoteric structure in nature. The increase of intracellular bioavailability of this drug thus becomes important for improving its antitumor activity. ##STR2##
Reports indicated that azatyrosine was synthesized via a seven-step synthetic route shown in Scheme 1 (Norton, S. J. et al J. Org. Chem., 1961, 26, 1495-8.) and a eight-step synthetic route shown in Scheme 2 (Makabe et al 2-273659 1989.). The Norton method used expensive kojic acid as starting material and multiple steps disclosed by Makabe et al lead to a low yield of azatyrosine. ##STR3##